The long-term objective of this project is to supply information which will aid in the identification of conditions under which individuals might be susceptible to organothiophosphate pesticide-induced toxicity. It seeks to accomplish this objective by focusing on how hepatic and extrahepatic metabolic activation and detoxification of these pesticides mediate their toxicity. The relative activation and detoxification of organothiophosphate pesticides at sites of entry and, after absorption, at various internal organs could greatly influence the severity and time course of their toxicity. Understanding the interactions of other foreign compounds with organothiophosphates following different routes of exposure requires knowledge of the relationships of metabolism of these pesticides by different tissues. This research will not only provide information helpful in the safety assessment of pesticides, but will also contribute to the fundamental knowledge of those metabolic systems involved in the biotransformation of these pesticides. Specific aims to be addressed in this research are: 1. To evaluate if the toxic oxygen analogs produced hepatically from organothiophosphates escape the liver, thereby entering the general circulation, or are these potent cholinesterase inhibitors further biotransformed hepatically, inactivating them before they exit the liver; 2. If the toxic oxygen analogs of organothiophosphates escape the liver and enter the blood, can they survive long enough to reach extrahepatic organs, or will they quickly be detoxified by plasma A-esterases; 3. To evaluate the toxicological significance of extrahepatic activation of organothiophosphate pesticides with particular emphasis on the brain.